Seeinstructions): Frontotemporal dementia (FTD), a devastating, rapidly progressive neurodegenerative disease, accounts for 15-20% of all dementia cases and particularly common in patients under 65 years of age. FTD patients suffer progressive neurodegeneration in the frontal lobes and other brain regions, resulting in behavioral changes, and memory and motor neuron deficits. Compared with other age-dependent neurodegenerative diseases, the molecular, cellular, and genetic bases of FTD are poorly understood, although there is increasing recognition of pathological overlap with other neurodegenerative diseases. Genetic causes are estimated to account for ~40% of FTD, and since 1998, dominant mutations in four causative genes have been identified. These include mutations of tau, valosin-containing protein (VCP), CHMP2B, and progranulin. The identification of these genes allows for the generation of sorely needed animal models of FTD. The overall goal of this proposal it to generate murine models for FTD, focusing on progranulin and VCP. Murine models will enable detailed study of the pathogenesis, testing of genetic interactions between contributing mechanisms, and testing of emerging therapies. Aim 1 is to generate mouse models for FTD caused by progranulin deficiency. Specifically, we will generate mice lacking progranulin in the whole body and, with Cre-LoxP methodology, in neurons and microglia. Additionally, we will generate mice that harbor a disease- specific nonsense mutation (corresponding to the human mutation R493X), which will provide a model for testing therapies that target non-sense mutations. Aim 2 is to generate transgenic mice expressing human VCP with an FTD mutation (R155H) in neurons. We will also test whether a genetic interaction exists between VCP mutations and Pgrn mutations by crossing the different models. The phenotypes of each of these potential disease models will be extensively analyzed, many aspects with the assistance of expert local collaborators.These.mouse models will enable us to complement on-going cell-based studies of disease pathogenesis with in vivo testing of emerging hypotheses. The mice will also be deposited in public repositories, making them generally available to the research community. RELEVANCE (Seeinstructions): Dementias due to progressive loss of brain function are huge health problems confronting our population. Frontotemporal dementia (FTD), a rapidly progressive and devastating disease, is less well known than Alzheimer's disease but is emerging as a relatively common cause of dementia. Currently, there are no cures and there are no proven animal models. We propose to generate mouse models of FTD, both to study how the disease occurs and to provide a means to test new therapies.